The benefits of long-term vitamin C consumption in excess of the U.S. government recommended daily allowance (RDA) are widely acknowledged and include reduced risks of cancer, cardiovascular disease, and cataracts. Higher than RDA vitamin C intakes have been associated with increases in HDL cholesterol, decreases in LDL cholesterol oxidation, decreased blood pressure, and decreased cardiovascular mortality. Vitamin C enhances non-heme iron absorption in individuals with low iron status. Helpfulness has been reported for severe attacks of ulcerative colitis, advanced human cancer, and reticulum cell sarcoma. Doses in these reports ranged from 50 to 150 gm intravenous per day, with no adverse effects reported. The manufacturers' literature states that doses as high as 6 gm per day has been administered without toxicity. High dose IV vitamin C has been used to treat optic neuritis, and was found to produce equivalent results to oral or intravenous corticosterone, or oral vitamin B12. No adverse events were encountered among 25 patients treated. The possibility of its working through its action on free radicals was raised.

Higher dose vitamin C (170 mg/kg/24 hours) was shown to have no adverse effects upon guinea pigs. These animals had 70% body surface area deep thermal burns. Animals receiving the vitamin C had lower water content of the burned skin, suggesting that postburn capillary permeability was minimized by the use of vitamin C. With even higher doses, the authors were able to reduce the 24 hour resuscitation fluid volume from 4 ml/kg/% burn to 1 ml/kg/% burn, while still maintaining adequate cardiac output. In contrast, with a lower dosage and measured only 5 hours after the injury, vitamin C infusions had no effect on graded scald produced burns, at least in terms of changes in microvascular permeability or in edema formation among dogs with hind-paw lesions. Pre-burn infusions did significantly attenuate burn-induced increases in paw weight gain, and no adverse reactions were encountered.

Oxidized LDL cholesterol (oxLDL) induced leukocyte adhesion to both microvascular and macrovascular (aortic wall) endothelium, can be prevented by pre-treatment of hamsters with oral or intravenous vitamin C. The mechanism of action was thought to be the scavenging of reactive oxygen species. Vitamin E and probucol did not show these effects.

Vitamin C Therapy (Studies):

Eight placebo-controlled, double blind studies and 6 non-placebo clinical trials have shown no adverse effects of vitamin C doses up to 10,000 mg consumed daily for up to three years. The possibility of any adverse effects of higher (multiple gram doses) has received considerable scrutiny. Despite concerns and several contradictory case reports, extensive searches have failed to produce any adverse effects. The exceptions occur among patients with renal insufficiency, patients on chronic hemodialysis, possibly patients with hemochromatosis and iron overload, and a subset of oxalate stone formers. One case report exists of acute oxalate nephropathy occurring in a patient with nephrotic syndrome and primary amyloidosis who was given 45 gm IV vitamin C as a bolus injection. Most protocols use slow infusions (25-50 gm/hr) and do not give high doses to patients with renal insufficiency. Nevertheless, definite causality was not established in this case report. Concerns about high dose vitamin C affecting uricosuria, vitamin B-12 destruction, mutagenicity, are calcium oxalate stones have not been substantiated despite careful and thorough searches.

A 42 year old male with widely disseminated, biopsy-proven reticulum cell sarcoma was treated with high dose (100mg infusion Vitamin C. He experienced two complete, spontaneous regressions of his illness coinciding exactly in time with, intravenous vitamin C administration. He remains alive 17 years later. Of course, placebo has been reported to accomplish as much (the drug krebazolin), but that patient died after his second spontaneous regression of cancer when he learned the the drug in which he so believed had been declared by the FDA to be worthless.

Vitamin C Therapy (Products):

Vitamin C (ascorbic acid) -is available in three size ampules -- 1 ml with 500 mg of vitamin C and 10 mg monothioglycerol, 10 ml with 1 g of sodium ascorbate, 0.5% monothioglycerol, and 25 ml with 25 gm sodium ascorbate. The pH of the solution is general buffered with sodium hydroxide or calcium carbonate. Sodium hydrosulfite 0.5% is often used as an antioxidant. The pH is buffered from 5.5 to 7.0, and the 500mg/ml solution has an osmolality exceeding 2000 mOsm/kg.

Vitamin C Therapy (Stability Issues):

Ascorbic acid gradually darkens on exposure to light. A slight color developed during storage does not impair the therapeutic activity. However, Abbott recommends protecting the intact ampuls from light by keeping them in the cartons until ready for use. HPLC analysis showed that ascorbic acid was stable at room temperature (23 degrees Centigrade) when protected from light, exhibiting less than a 10% loss. Exposure to light results in losses of approximately 50 to 65%. Although refrigeration is recommended, Lilly has stated that its ascorbic acid injection has a maximum room temperature stability of 96 hours. Intact ampuls of commercial ascorbic acid injection (Vitarine) have been reported to be stable for four years at room temperatures not exceeding 25 degrees C. Ascorbic acid is rapidly oxidized in air and alkaline media.

Other studies of vitamin C in parenteral nutrition solutions have shown no loss of activity so long as the mixture is protected from light. A 35% loss of activity was seen at 39 hours when the mixture was exposed to light continually. Thirty to forty percent of vitamin C activity was lost after 24 hours when ascorbic acid was added to parenteral nutrition solutions consisting of amino acids, dextrose, electrolytes, multivitamins, and trace minerals in 3 liter PVC bags stored at 3 to 7 degrees C. The degradation slowed as the oxygen supply was reduced to the diffusion through the bag. About a 55 to 65% loss of activity was reported after 7 days of storage. The oxidation of the ascorbic acid was catalyzed by metal ions, especially copper. In the absence of copper, less than 10% loss of activity occurred at 24 hours. No immediate incompatibility or precipitation was observed over the 7 days.

In another parenteral nutrition solution composed of amino acids (Kabi-Vitrum), dextrose 30%, and fat emulsion 20% (Kabi-Vitrum) in a 2:1:1 ratio with electrolytes, trace elements, and both fat- and water-soluble vitamins, no significant loss of activity of retinyl palmitate, alpha tocopherol, thiamine mononitrate, sodium riboflavin-5'-phosphate, pyridoxine HCl, nicotinamide, folic acid, biotin, sodium pantothenate, and cyanocobalamin were found at 96 hours when the solution was stored in darkness at 2 to 8 degrees C. Sodium ascorbate and its biologically active degradation product, dehydroascorbate, totaled 59 and 42% of the starting concentration at 24 and 96 hours, respectively. No precipitation or incompatibilities were found. No significant loss of activity was found in a simulated infusion over 24 hours at room temperature without light protection. This procedure did increase the decomposition rate of vitamin C, however, with ascorbate showing 51% concentration and dehyrdroascorbate showing 65% concentration. Light protection did not significantly change this degradation rate at room temperature.

HPLC analysis of the stability of vitamin C in parenteral nutrition solutions with and without fat emulsions showed retention of 90% vitamin C content for 12 hours when the solutions were exposed to fluorescent light and for 24 hours when they were protected from light. Storage in a cool, dark place resulted in retention of activity for 7 days.

Ascorbic acid loss was studied with MVI-12 (Armour) admixed in parenteral nutrition solutions containing different amino acid products, with or without Intralipid 10%, and stored in either glass bottles or PVC bags, either refrigerated or at room temperature. Ascorbic acid was lost under all conditions at room temperature and not at refrigerated temperature. Losses were greater in PVC bags than glass bottles. No immediate incompatibilities or delayed precipitations were found.

One can conclude from all these studies that some loss of vitamin C activity is inevitable and that it is prevented by light protection, preparing mixtures for infusion as close as possible to the time of infusion, and by giving higher concentrations of vitamin C than needed, to counteract degradation. Since no physical incompatibilities were found, giving higher concentrations seems logical, especially when trace minerals are found in the solution. The higher the mineral content of the solution and the longer from time of preparation to administration, probably the higher the vitamin C content should be. Further studies are needed in clinical settings to determine the extent of degradation expected and the amounts of vitamin C which should be given (at different mineral concentrations) to achieve desired dosing.

Intravenous Infusions: Studies of Multiple Nutrients:

In support of a molecular explanation of the perceived clinical benefit reported by patients who receive intravenous vitamin infusions, especially vitamin C, beneficial changes in erythrocyte ATP/ADP ratios after infusion have been reported. The effect was to normalize the ratio. Low ratios increased, and high ratios decreased. Control subjects were unaffected and the results were statistically significant. No adverse effects were seen in this study on patients receiving high-dose intravenous vitamins.

Intravenous B Vitamin Infusion:

Up to 40% of cancer patients receiving parenteral nutrition were deficient in vitamins B1, B2, B6, and niacin, despite receiving the recommended daily doses of 3mg, 3.6 mg, 4 mg, and 40 mg, respectively. Even at twice the recommended daily doses, these deficiencies did not disappear. They concluded, "since intravenous doses of B1, B2, B6, and niacin are safe and well tolerated, it appears that increased daily amounts of these vitamins should be given to cancer patients on parenteral nutrition.

Thiamine. Three patients who developed Wernickes encephalopathy despite being given intravenous thiamine have been reported. These authors suggested that the amount of intravenous thiamine commonly given is much too low.

Therefore, we propose that the PT Committee allow us to increase the amount of Vitamin C given to the 2 gm to 25 gm range, depending upon the patient.